Multi column chromatography system

ABSTRACT

The present invention relates to a method and apparatus for chromatographically analyzing each of a plurality of samples in detector, comprising an autosampler to contain a plurality of samples for chromatographic analysis and a plurality of chromatographic systems, each system comprising one or more pumps and one or more chromatography columns. A detector is included for detecting compounds in the samples from each of the chromatography systems along with a valve positioned between the detector and the plurality of chromatography systems, the valve permitting each sample to reach the detector in sequence. A computer control device is included which adjusts the introduction of samples from the autosampler into the plurality of chromatography systems as well as the position of the valve to sequentially separate and deliver compounds within the samples to the detector.

FIELD OF THE INVENTION

[0001] The present invention relates to a multi-column chromatographysystem, particularly suitable for high performance liquid chromatography(HPLC). The system optimizes a detector's data gathering ability, suchas a mass spectrometer (MS), without sacrificing the quality or quantityof data collected. The system operates via the use of a staggeredHPLC-MS operation sequence, through a plurality of individualchromatography systems as directed by a programmed computer protocol,and is suitable for both turbulent flow and laminar flow type systems.

BACKGROUND OF THE INVENTION

[0002] U.S. Pat. No. 5,919,368, owned by the assignee herein, providesan excellent review regarding the utility of separations by highperformance liquid chromatography. As noted therein, the separationprocess relies on the fact that a number of component solute moleculesin a flowing stream of a fluid percolated through a packed bed ofparticles, known as the stationary phase, can be efficiently separatedfrom one another. The individual components are separated because eachcomponent has a different affinity for the stationary phase, leading toa different rate of migration for each component and a different exittime for each component emerging from the column. The separationefficiency is determined by the amount of spreading of the solute bandas it traverses the bed or column.

[0003] The '368 patent ultimately goes on to describe an improved methodof performing liquid chromatography comprising the steps of packingwithin a tubular container a substantially uniformly distributedmultiplicity of rigid, solid, porous particles with chromatographicallyactive surfaces, so as to form a chromatographic column having aninterstitial volume between said particles, said particles havingaverage diameters of not less than 30 μm and loading said surfaces withat least one solute that is reactive with said surfaces, by flowing aliquid mixture containing said solute through said column at a velocitysufficient to induce flow of said mixture within at least a substantialportion of said interstitial volume at a reduced velocity greater thanabout 5000. The aforementioned method: 1. dramatically enhances both thespeed and capacity of both analytical and preparative chromatography forboth small and large molecules such as biologicals and the like; 2. isoperative with mobile phase velocities considerably greater than anypreviously employed with significantly improved results; 3. makes use ofpacked particle beds in which the particles are substantially largerthan those previously used in the art; and 4. offers a process that isoperative at pressures considerably below those taught by the prior artfor turbulent flow chromatography. In that regard, attention is alsodirected to U.S. Pat. Nos. 5,772,874; 5,795,469; 5,968,367; 6,110,362and 6,149,816, also owned by the assignee herein, which disclose otherassociated methods and apparatus for use in high performancechromatography applications.

[0004] With the above in mind attention is now directed to U.S. Pat. No.6,066,848 which is said to provide a method and system for analyzing thecomposition of a plurality of fluid samples by chromatographictechniques. More specifically, the '848 patent states that the inventiontherein is able to distinguish between each of a plurality of fluidsamples simultaneously electrosprayed from parallel liquidchromatography columns towards a miss spectrophotometer such that themass spectra associated with each fluid sample can be reliabledetermined. That is, the '848 patent goes on to describe that aplurality of fluid samples are simultaneously separated by parallelliquid chromatography columns and are simultaneously electrosprayedtowards an entrance orifice of a mass spectrophotometer. A blockingdevice having an aperture passing therethrough is positioned so as toblock all but one of the fluid samples from passing into the entranceorifice of the mass spectrophotometer at any moment in time.

[0005] However, various problems have been identified with the aboveidentified technique, which has in various forms be referred to as a“MUX” (i.e. multiplexed) liquid chromatography/mass spectrometry system.For example, such technology generally makes use of one pump to drivefour sample streams. As a consequence, it is difficult to achieveoptimum pressure in all streams, the back pressure may vary with columnpacking, the back pressure may vary with use, there can be poorreproducibility between streams, and there is a standing problem of“drift”. Expanding upon this, there is no back-pressure Monitoring,there is no way to link samples to a specific column, and when a singlestream shuts down, e.g., in a four-column system, 25% of the data islost along with 25% of the samples.

[0006] In addition, MUX technology, which makes use of a blocking disk,creates a potential for carryover as each spray impinging upon the diskmay become cross contaminated. Furthermore, analyte date readout, byvirtue of being multiplexed, leads to the feature that each of theelectrosprays is analyzed over and over again in sequence. Accordingly,a varying mass spectrum reading will be generated for each of theplurality of fluid sample electrosprays over time. That being the case,MUX analyte data readout will appear as shown in FIGS. 1 and 2 herein,which makes clear that the number of data points is, in all cases,limited by the sampling rate of such a multiplexed system. Morespecifically, as shown in FIG. 1, data points are a function of samplingrate and are illustrated for sprays 1-4 v. elapsed time. FIG. 2 thenillustrates that as a consequence of such multiplexing, the reportedpeak possibilities are prone to error, as different peaks may be drawn(dotted v. solid line) for the multiplexed data points so collected.

[0007] Stated another way, the MUX system can lead to insufficient peakdata points for tracing along with a sacrifice in precision andsensitivity when operated at faster speeds. Furthermore, such problemsare compounded in the case of multiple analytes.

[0008] Accordingly, there remains a need to develop a multi-columnchromatography system that overcomes the disadvantages of the prior artand which provides a more reliable and accurate chromatographicseparation along with maximum use of a detector's data gatheringability.

SUMMARY OF THE INVENTION

[0009] A method and apparatus for chromatographically analyzing each ofa plurality of samples in a detector, including an autosampler whichcontains a plurality of samples for chromatographic analysis, aplurality of chromatography columns, a plurality of pumps associatedwith said plurality of columns to establish a flow of eluant from eachof said plurality of columns and a detector for detecting compounds insaid eluant from each of said columns. The apparatus further includes avalve positioned between said detector and said flow of eluant from saidcolumns, said valve permitting each flow of eluant to reach the detectorin sequence. A computer control device is included which automaticallyadjusts the introduction of samples from the autosampler into saidplurality of columns as well as the position of said valve tosequentially deliver said eluant to said detector.

[0010] In alternative embodiment, the present invention relates to anapparatus and method for chromatographically analyzing each of aplurality of samples in detector, comprising an autosampler to contain aplurality of samples for chromatographic analysis and a plurality ofchromatographic systems, each system comprising one or more pumps andone or more chromatography columns. A detector is included for detectingcompounds in said samples from each of said chromatography systems alongwith a valve positioned between said detector and said chromatographysystems, said valve permitting each sample to reach the detector insequence and a computer control device which adjusts the introduction ofsamples from said autosampler into said chromatography systems as wellas the position of said valve to sequentially separate and deliver saidcompounds within said samples to said detector. Each chromatographicsystem is independent of the others, and each may consist of a number ofcomponents, including pumps, columns, valves, and heaters.

[0011] In a still further embodiment, the present invention relates to achromatographic system containing a column, including a pump for elutinga mobile phase, and a detector for detecting compounds flowing out ofsaid column, the improvement which comprises a computer control devicethat: (i) collects pressure readings over time from said pump to providea tracing, (ii) compares such tracing to a stored pressure v. timetracing for said pump and (iii) elects to shutdown said pump when saidtracing deviates from said stored tracing.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 illustrates the prior art analyte read-out for amultiplexed (MUX) HPLC system.

[0013]FIG. 2 illustrates the prior art peak measurement possibilitiesfor a multiplexed (MUX) HPLC system.

[0014]FIG. 3 illustrates in schematic view the multi-columnchromatography system of the present invention.

[0015]FIG. 4 illustrates sampling points and peak profile as a result ofthe multi-column chromatographic system of the present invention.

[0016]FIG. 5 illustrates the typical results of the multi-columnchromatography system of the present invention.

[0017]FIG. 6 illustrates in block diagram format the functionality ofthe software system protocol of the present invention operating withinthe computer controller as applied in part to control of theautosampler.

[0018]FIG. 7 further illustrates in block diagram format thefunctionality of the software system protocol of the present inventionoperating within the computer controller as applied in part to initiatedata collection at the detector.

[0019]FIG. 8 illustrates in block diagram format the functionality ofthe software system protocol of the present invention as applied to themonitoring of system pressure.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] One schematic view of the multi-column chromatography system 10of the present invention is shown in FIG. 3. As can be seen therein, thesystem 10 contains an autosampler which includes a plurality ofinjection valves 14, a plurality of pumps 16, a plurality of columns 18,a selector valve 20 and a detector 22. Columns 18 may comprise a widevariety of columns useful for chromatographic analysis which can be usedto direct a fluid sample into the entrance orifice of a given detector.For example, columns 18 may comprise high performance HPLC columns,capillary electrophoresis columns, gas chromatography columns, flowinjection transfer lines, etc. In addition, although not shown, thesystem may also preferably includes a port valve, positioned before thecolumns, which in the case of a single column system (one or more pumpsand one or more columns) operates to load sample in one direction, andelute in the opposite direction. In the case of a two column system, theport valve provides a similar function, and also provides a loop foreluting solvent.

[0021] However, as noted above, the present invention may also bedescribed as an apparatus and method for chromatographically analyzingeach of a plurality of samples in detector, comprising an autosampler(with preferably two sampling arms) which contains a plurality ofsamples for chromatographic analysis, along with a plurality ofchromatographic systems, each system comprising one or more pumps andone or more chromatography columns. In that regard, it can beappreciated that each chromatographic system is controlled by thecomputer controller herein to ensure that samples are introduced by theautosampler to avoid overlap at the detector end, and to ensure maximumuse of the detector's time as a detector. In that regard, the inventionherein preferably relates to the use of, e.g., four (4) independentchromatography systems, wherein each system contains one (1) or morepumps and one (1) or more columns. Alternatively, in a more preferredembodiment, the invention herein relates to the use of four (4)independent chromatography systems, wherein each system contains two (2)pumps and one (1) column, such that one pump is devoted to loading thecolumn with sample, and one pump for elution. As such, the inventionherein preferably relates to the use of either of such previouslymentioned options, to the extent that at least two (2) of thechromatography systems so defined are incorporated into the sequencingchromatography apparatus of the present invention.

[0022] As can next be seen in FIG. 4, according to the presentinvention, the number of data points 24 available in the presentinvention is consistent with the number of data points available from astandard single-column/single detector configuration. That is, thenumber and quality of data points 24 from a column chromatographyprocedure are undisturbed in the present invention, since the presentinvention relates to the unique sequential operation of a plurality ofchromatography systems such that a given point in time such that qualityand quantity of data is not sacrificed. As can be seen in FIG. 4,according to the present invention, curve 28 is generated, whichrepresents a more precise curve fitting than that which may be obtainedby the multiplexed system of the prior art, which inherently containsfewer data points as well as-the possibility to report less precisecurve 26. In that regard, it is worth noting that no matter how fast amultiplexed system is sampling, the invention herein will, e.g., in caseof a four (4) samples to be analyzed, report four times more information(data points) for any given peak.

[0023] Expanding upon the above, attention is directed next to FIG. 5,which illustrates curves 30, 32, 34, and 36, as obtained herein, due toprocedural benefit of controlled staggered/sequenced injections. As canbe seen, the detector analyzes each curve in sequence. In such regardthe detector herein functions to detect and report curve 30, while thosesamples responsible for curves 32, 34, and 36, although in the processof being eluted in the column, have not yet exited from the column. Suchprogrammed chromatography sequencing is provided herein by a computercontrol device which, upon consideration of when the target sample islikely to exit the column, adjusts the introduction of samples from theautosampler into the columns to sequentially deliver eluant containingsample for sequenced detection. In other words, the computer controllerherein considers the samples in the autosampler, and the input ofinformation concerning their anticipated data-collecting window at thedetector, and selects those samples from the autosampler forintroduction into the system to maximize detector use.

[0024] The computer control device of the present invention thereforeadjusts the introduction of sample from the autosampler, as well as theposition of valve 20 (FIG. 3) to sequentially deliver eluant to thedetector. However, the computer control device herein preferablyfunctions to provide other important blocks of information to the user.This is more specifically illustrated in FIG. 6, which provides aschematic overview of the functionality of the software system protocolwithin the computer control device of the present invention as appliedto the autosampler. As shown therein, the control device first checksthat the autosampler/probe is ready to start a sample and thatsufficient time has passed since the last sample start. The controllerthen checks that a chromatographic system as herein defined is ready toaccept a sample. This is determined by the time remaining for thecurrently running elution protocol, and this prediction thereinoptimizes the overall system efficiency. By contrast, waiting for thechromatography system to indicate that it is “ready” before starting thesample would elongate the cycle time by that amount of time betweenstarting the sample and the sample being “ready” to inject.

[0025] The controller then determines which sample corresponds with the“ready” chromatography system. When sample information is entered, theuser has the option of specifying a particular chromatography system orallowing any of the available systems to be used for the sample. Thesample is then started and when the sample is ready to inject, thecontroller will verify that the chromatography system is ready and thatinjection will not cause the new data window (i.e., the ensuing reportof the chromatographic peaks) to overlap the previously injected sampledata windows.

[0026]FIG. 7 illustrates the detector and selector valve control of thepresent invention. As shown therein, the controller checks that achromatographic system elution protocol (“method”) has progressed to thestart “data window time” as specified by the current method. Theselector valve is then moved to deliver the fluid stream of thechromatographic system to deliver sample to the detector and thedetector is signaled to begin data collection.

[0027]FIG. 8 illustrates the pressure control of the invention herein asprovided by the computer controller. More specifically, the controllerwill collect back pressure readings for each pump 14 in eachchromatography system at an average rate of 10 data points per second.As noted above, the chromatography system herein refers to one or morepumps and one or more chromatography columns within the disclosedchromatography apparatus.

[0028] The computer controller therefore maintains a running average forthe pressure for each pump in each system. The controller then comparesthat running average to a history for that pump in each system anddetermines whether or not deviation exists that would warrant ashutdown. In a related manner, the controller maintains a runningaverage for the pressure for each type of pump in the system, i.e.,loading pumps or eluting pumps. The controller again compares thatrunning average to a history for that pump in each system and againdetermines whether or not deviation exists that would warrant ashut-down.

[0029] The controller herein also compares each newly collected sampleto the average of pressure for that pump for the previous run. Thecontroller then generates offset and correlation data for that newlycollected sample. In other words, the controller identifies whether ornot the data points vary in intensity and location (i.e., that point intime) from the average pressure v. time tracing generated from one ormore previous runs. The controller then determines whether or not thegenerated offset and correlation values or tracings are withinacceptable limits. In a preferred embodiment, when the generatedpressure v. time tracing deviates from the stored tracing by, e.g. theslope or shape of the tracing between at least two pressure readings,the system may be shutdown.

[0030] In addition, and in related context, the controller also compareseach new collection of sample back-pressure data points for a given pumpto the running average based upon pump type. Once again, the controllergenerates offset and correlation data, and determines whether or not thegenerated offset and correlation values are within acceptable limits. Ifoffset and correlation values for the pump are outside of a userselected range, sample introduction into the system is suspended.

[0031] Finally, if offset and correlation values for a given system areoutside of user selected ranges when compared to other chromatographysystems (when such other systems are running the same sample and elutionprotocol) sample introduction on the system will also be automaticallysuspended.

[0032] One particularly preferred column herein, but by no meanslimiting, are those columns which include a substantially uniformlydistributed multiplicity of rigid, solid, porous particles withchromatographically active surfaces, said particles having averagediameters of greater than about 30 μm, the interstitial volume betweensaid particles being not less than about 45% of the total volume of saidcolumn; and means for loading said surfaces with at least one solutethat is reactive with said surfaces, by flowing a liquid mixturecontaining said solute through said body at a velocity sufficient toinduce flow of said mixture within at least a substantial portion ofsaid interstitial volume at a reduced velocity greater than about 5,000.

[0033] To these ends the present invention is directed to the use of achromatography column or body in the sequenced chromatography systemherein that is formed as a substantially uniformly distributedmultiplicity of rigid, solid, porous particles having substantiallyuniform mean cross-section dimensions or diameters of not less thanabout 30 μm, typically 50 μm or greater up to, but not limited to, 1000μm in certain instances as will be delineated hereinafter. The term“particle” as used herein should not be construed as limited to anyparticular form or shape, regardless of symmetry or lack thereof, aspectratio, regularity and the like. The term “solid” as used herein, isintended to refer to the physical state of the matter and should not beconstrued to exclude porous particles. The particles are selected from arange of various sizes and shapes and are held together in a body orcolumn as by pressure, sintering and the like so that interstitialchannels having a total interstitial volume of not less than about 45%of the total volume of the column are formed between the particles. Thesurfaces of the particles, including the inner surfaces of the pores inthe particles, may be chromatographically active, as by being coatedwith chromatographic stationary phase layers. This method includes thestep of flowing through the column a fluid mixture containing at leastone solute or suspended phase that is interactive with the particles'surfaces in order to load the column. Because of the nature of theparticles and packing in the column, the flow of the fluid mixturethrough the column can be at a high flow rate, preferably at an averagereduced velocity (i.e., ud[p]/D wherein “U” is the mobile phasevelocity, “d[p]” is the packing particle diameter and “D” is thediffusion coefficient in the mobile phase) greater than about 5000, andincluding, in certain instances to be described hereinafter, reducedvelocities values as high as 70,000 or higher. It is believed that undersuch conditions, turbulent flow of the mixture is induced within atleast a major portion of the interstitial volume, and it is postulatedthat such turbulent flow in fact enhances the rate of mass transfer,thus increasing the dynamic capacity of the column.

[0034] The particles described above are preferably formed frommaterials that are incompressible, which term is to be understood tomean that the time rate of changes of the densities and volumes of theparticles under pressures of at least about 5×10<3> psi, (includingoutlet column frit retainer) remains substantially zero, and theparticles therefore will substantially resist plastic deformation evenat such high pressure. The particles are shaped and selected in a rangeof sizes and shapes such that they can be packed at a pressuresufficient to form a column characterized in having interstitialchannels formed between the particles. Because of the irregularity ofthe particles, it will be recognized that the interior walls of suchchannels are necessarily quite rough in configuration. While it isbelieved that at least the majority of channels have mean cross-sectiondiameters substantially not less than about 4 μm, the interstitialvolume fraction (i.e. the total volume of interstitial channels betweenthe particles) should not be less than about 45% of the total volume ofcolumn. It will be appreciated that typical columns have interstitialvolume fractions less than about 45%, more particularly ranging fromabout 35% to 42%. The surfaces of particles are chromatographicallyactive either per se as is well known in the art, or by treatment, as bycoating, with any of the many known chromatographically active,stationary phase layers, also as well known in the art.

[0035] As noted, in order to insure the formation of the desired uniformdensity column with the preferred interstitial fraction and precludecollapse under operating pressure, the particles used to pack a columnfor use in the present invention of sequenced chromatography analysismay include rigid solids that must necessarily be incompressible atpacking pressure of at least about 5×10³ psi, preferably up to pressuresas high as about 1×10⁴ psi. To that end, the preferred particles areformed from materials such as alumina, titania, silica, zirconia,vanadia, carbon, various relatively inert metals, and combinationsthereof.

[0036] In that regard, the chromatography column used herein may includecolumns used under conventional laminar flow regimes. The columns maytherefore be constructed of particles, which due to a lack of requisiterigidity are run at low flow rates and pressure drops. Such particlesmay have average particle sizes less than about 30 microns and as smallas about 1 micron. It is understood that under these operatingconditions, the analysis times are relatively long and the reducedvelocities may be as small as 1.

[0037] In addition, the invention herein may include the use of asubstantially uniform, elongated chromatography column containingchromatographically reactive surfaces, means for injecting into saidcolumn a discrete volume of liquid mixture containing at least onesolute that is reactive with said surfaces so as to load said column,and means for flowing eluant fluid through said loaded column, whereinthe means for flowing said eluant fluid comprises means for injecting atleast one discrete plug of said eluant fluid into said column adjacentthe input of said column so as to maintain minimized spatial stepseparation between said plug and said discrete volume of liquid mixtureas said plug and volume traverse the column wherein said column and saidmeans for flowing are configured such that the flow of said volume ofeluant traverses said column at a reduced velocity greater than about5000.

[0038] The invention herein is also applicable to chromatography columnshaving chromatographically reactive surfaces, including the steps offlowing through said column a discrete volume of a liquid mixturecontaining at least one solute that is reactive with said surfaces, andeluting from said surfaces said solute bound thereto, by flowing eluantfluid through said column, comprising the steps of injecting at leastone discrete volume of an eluant fluid into the flowstream in saidcolumn such as to maintain minimized spatial separation between saiddiscrete volumes as the latter traverse said column at a reducedvelocity great than about 5,000.

[0039] The invention herein is also applicable to separating relativelylow molecular weight compounds from compounds having relatively highmolecular weights substantially an order of magnitude greater or morethan said low molecular weight compounds in a liquid mixture of saidcompounds, comprising a chromatographic body formed of substantiallyuniformly distributed multiplicity of rigid, solid, porous particleswith average diameters of not less than about 30 μm, and average porediameters sufficiently small to substantially exclude introduction ofsaid compounds of relatively high molecular weight into said pores, thesurfaces of said particles and pored being hydrophobic andchromatographically active, and a means for flowing said mixture at avelocity sufficient that the flow of said mixture within at least asubstantial portion of the interstitial volume between said particles isat a reduced velocity greater than about 5,000 until said high molecularweight compounds have exited said body, and a means for eluting saidrelatively low molecular weight compounds from said body with an eluantliquid at a reduced velocity less than about 5,000, after said highmolecular weight compounds have exited from said body.

[0040] With consideration now shifted to the detector 22, such ispreferably any type of detector that is employed in chromatographysystems to detect the samples eluted through the columns. Those skilledin the art will therefore recognize that detector 22 may comprise anultraviolet detector, or more preferably, a mass spectrophotometer. Thedetector therefore provides identification of the desired componentcompounds of a sample by determining exactly when such a desiredcomponent compound is eluted from the exit end of the column.

[0041] The invention herein is suitable for any type of chromatographytype configuration making use of a multiple column configuration. Inthat regard, the invention herein is applicable to analyticalchromatography as well as preparative chromatography systems. In thatregard, the invention is applicable herein to conventional HPLC systemsrelying upon a mass spectrometer detector which system undergoesconventional programmed liquid flow velocities and makes use ofconventional type gradient systems. However, while such use ofconventional chromatography systems is suitable herein, the inventionherein advances the efficiency of such known systems by uniquely linkingup a plurality of such systems to a single detector to optimize thedetectors data gathering ability without sacrificing the quality orquantity of data collected.

What is claimed is:
 1. An apparatus for chromatographically analyzingeach of a plurality of samples in detector, comprising: (a) anautosampler to contain a plurality of samples for chromatographicanalysis; (b) a plurality of chromatographic systems, each systemcomprising one or more pumps and one or more chromatography columns; (c)a detector for detecting compounds in said samples from each of saidchromatography systems; (d) a valve positioned between said detector andsaid chromatography systems, said valve permitting each sample to reachthe detector in sequence; and (f) a computer control device whichadjusts the introduction of samples from said autosampler into saidchromatography systems as well as the position of said valve tosequentially deliver said compounds in said samples to said detector. 2.The apparatus of claim 1 wherein each chromatography system includes 4pumps and 4 columns.
 3. The apparatus of claim 1 wherein eachchromatography system includes 8 pumps and 4 columns.
 4. The apparatusof claim 3, wherein each column contains one pump for loading sample andone pump for eluting.
 5. The apparatus of claim 1 wherein saidchromatography columns include a substantially uniformly distributedmultiplicity of rigid, solid, porous particles with chromatographicallyactive surfaces, said particles having average diameters of greater thanabout 30 μm, the interstitial volume between said particles being notless than about 45% of the total volume of said column; and means forloading said surfaces with at least one solute that is reactive withsaid surfaces, by flowing a liquid mixture containing said solutethrough said body at a velocity sufficient to induce flow of saidmixture within at least a substantial portion of said interstitialvolume at a reduced velocity greater than about 5,000.
 6. The apparatusof claim 1 wherein said detector is a mass spectrometer.
 7. Theapparatus of claim 1, wherein said computer control device collectspressure readings from each of said pumps and compares such readings tostored pressure readings and elects to shutdown one or more of saidpumps when said readings deviate from said stored pressure readings. 8.The apparatus of claim 7 wherein said pressure readings further comprisereading of pressure data points over a period of time for each of saidpumps.
 9. An apparatus for chromatographically analyzing each of aplurality of samples in a detector, comprising: (a) an autosampler tocontain a plurality of samples for chromatographic analysis; (b) aplurality of chromatography columns; (c) a plurality of pumps associatedwith said plurality of columns to establish a flow of eluant from eachof said plurality of columns; (d) a detector for detecting compounds insaid eluant from each of said columns; (e) a valve positioned betweensaid detector and said flow of eluant from said columns, said valvepermitting each flow of eluant to reach the detector in sequence; and(f) a computer control device which adjusts the introduction of samplesfrom said autosampler into said plurality of columns as well as theposition of said valve to sequentially deliver said eluant to saiddetector.
 10. The apparatus of claim 9 wherein said detector is a massspectrometer.
 11. The apparatus of claim 9 wherein said plurality ofcolumns comprises at least four columns.
 12. The apparatus of claim 9wherein said valve positioned between said detector and said flow ofeluant from said columns either selectively flows eluant from one ofsaid plurality of columns to said detector, while simultaneously flowingeluant from other of said plurality of columns to a collector.
 13. Theapparatus of claim 9 wherein said columns include a substantiallyuniformly distributed multiplicity of rigid, solid, porous particleswith chromatographically active surfaces, said particles having averagediameters of greater than about 30 μm, the interstitial volume betweensaid particles being not less than about 45% of the total volume of saidcolumn; and means for loading said surfaces with at least one solutethat is reactive with said surfaces, by flowing a liquid mixturecontaining said solute through said body at a velocity sufficient toinduce flow of said mixture within at least a substantial portion ofsaid interstitial volume at a reduced velocity greater than about 5,000.14. A method of chromatographically analyzing each of a plurality ofsamples in a detector, comprising (a) providing an autosampler tocontain a plurality of samples for chromatographic analysis; (b)providing a plurality of chromatography columns; (c) providing aplurality of pumps associated with said columns to establish a flow ofeluant from each of said plurality of columns into said detector; (d) avalve positioned between said detector and said flow of eluant from saidcolumns, said valve permitting each flow of eluant to reach the detectorin sequence; and (e) providing a computer control device which adjuststhe introduction of samples from said autosampler into said plurality ofcolumns as well as the position of said valve to sequentially deliversaid eluant to said detector.
 15. The method of claim 14 wherein saidcomputer control device selects that point in time for introduction ofeach of said plurality of samples into said columns based upon inputinformation, said input information indicating that point in timewherein said samples eluting from said column will exit said columns fordetection by said detector.
 16. The method of claim 14 wherein saidcolumn is packed with a substantially uniformly distributed multiplicityof rigid, solid, porous particles with chromatographically activesurfaces, so as to form a chromatography column having an interstitialvolume between said particles, said particles having average diametersof not less than about 30 μm; and loading said surfaces with at leastone solute that is reactive with said surfaces, by flowing a liquidmixture containing said solute through said column at a velocitysufficient to induce flow of said mixture within at least a substantialportion of said interstitial volume at a reduced velocity greater thanabout 5,000.
 17. In a chromatographic system containing a column,including a pump for eluting a mobile phase, and a detector fordetecting compounds flowing out of said column, the improvement whichcomprises a computer control device that: (i) collects pressure readingsover time from said pump to provide a pressure v. time tracing, (ii)compares such tracing to a stored pressure v. time tracing for saidpump; and (iii) elects to shutdown said pump when said tracing deviatesfrom said stored tracing.
 18. The chromatographic system of claim 17,wherein said tracing deviates from said stored tracing by the slope orshape of the tracing between at least two pressure readings.